Summary of work: The neuroanatomic and neurophysiologic underpinnings of age-associated cognitive and memory change remain unclear, as there is little information on longitudinal brain changes in the scientific literature. We are performing annual magnetic resonance imaging (MRI), positron emission tomography (PET), and neuropsychological assessments over 9 years in participants from the Baltimore Longitudinal Study of Aging (BLSA), aged 55 and older, to investigate the neurobiological basis of memory change. These evaluations will allow us to examine changes in brain structure and function which may be early predictors of cognitive change and impairment, including Alzheimer's Disease. An understanding of these associations and early detection of brain changes will be critical in identifying individuals likely to benefit from new interventions. In addition, we are using neuroimaging tools to investigate brain changes in response to estrogen and testosterone therapy in older women and men, respectively, from a local retirement community. These recently initiated studies are a follow-up to our observations that estrogen may protect against memory change and Alzheimer's Disease in post-menopausal women. We have examined the effects of age, sex, and apolipoprotein E (ApoE) genotype on brain structure measured by magnetic resonance imaging (MRI) during the first 2 years of the neuroimaging study of BLSA participants. Cross-sectional analyses from 104 participants who completed two annual MRI assessments reveal significantly greater atrophy in older (age 70-85) compared with younger (age 55-69) participants and in men compared with women. Measurements of regional brain volumes show that the effects of age and sex are not uniform across brain regions. Age differences are greatest for the temporal region and smallest for the occipital region. Sex differences are larger for parietal and occipital regions than frontal and temporal regions. The presence of an ApoE 4 allele, a putative risk factor for Alzheimer's Disease, is associated with reduced temporal and parietal brain volumes. Analysis of one-year longitudinal change indicates no detectable one-year change in total or regional brain volumes. In contrast, there is a small but significant increase in ventricular volume over the one-year interval. Associations between these brain changes and cognitive and memory change will be investigated as the longitudinal study progresses.